Piperidine: psycho-chemotherapeutic



United States Patent 3,035,977 PIPERIDINE: PSYCHO-CHEMOTHERAPEUTIC Leo George Abood, Oak Park, Ill. No Drawing. Filed Dec. 3, 1959, Ser. No. 856,896 6 Claims. (Cl. 167-65) The present invention is concerned with a new method of treating certain anxiety stages and similar mental tensions by chemical means and to composition dosage forms.

In the past, the more severe mental disorders or nervous disturbances have been frequently treated by physical shock therapy such as electroshock or chemical shock therapy such as caused by insulin. In the more recent past, certain synthetic chemicals and alkaloid extracts have been used in relieving patients from anxiety stages varying from mild to severe.

A new method has now been found to treat such mental tensions by administering to a patient in dosage form nontoxic, dissociable acid addition salts of piperidine. Such treatment results in relaxation of tensions, relief of anxiety stages, relief from hallucinations, and generally improved disposition. This effect can be observed in animals by a series of tests such as initially developing mental stress by modifying previously trained habit patterns and thereafter administering one of the above piperidine salts. Thus, a strain is placed on a habit pattern and is increased to a point at which certain objective signs of disquietude or other physical imbalance can be observed and measured, and under such conditions the new treatment method may be tried and studied. Also, for example, rats and monkeys with normal or experimentally caused viciousness, adjust well to their surrounding after the new treatment.

The new treatment, as mentioned above, consist in administering non-toxic, dissociable piperidine acid addition salts in dosage form to a living subject with the above outlined disturbances. Among useful salts are inorganic and organic acid addition salts such as the acetate, the hydrochloride, the sulfate, the tartrate, the citrate, the succinate, the phosphate, the maleate, the benzoate, the gluconate, the ascorbate, the lactate, the phthalate, etc. however, it should be emphasized that these are acid addition salts and the effective dosage is to be calculated on the basis of the free piperidine.

The new method of treatment may be carried out with any dosage form, i.e., the desired results may be accomplished by oral, intravenous, intramuscular, intraperitoneal, or subcutaneous administration of the new drug. Obviously, in treatments of humans, the oral administration is preferred due to its simplicity whereas in animal studies, administration by various injection routes are sometimes easier to control.

Where the oral route is selected, the piperidine salt is pressed into tablet form or may be processed into gelatin capsules. Tablets or capsules may include other nontoxic ingredients ordinarily used for such preparations, e.g., fillers, adjuvants, carriers, flavoring agents, coloring agents, etc. In case of tablets, any form of tablet coating may be selected but subcoating may be required for protection of some of the salts from moisture. Obviously, the solid salts may also be used for the various injection routes together with physiologically acceptable solvents, diluents, carriers, etc. Solution concentrations of about 125 mg./cc. are best suited, although somewhat higher concentrations are acceptable with the more soluble salts; lower concentrations are also operable where the salt is of lower solubility and the required dosage is small.

The effective dosage for treating mental tensions and anxiety with piperidine salts varies, of course, with the degree of the disturbance to be treated and the route of administration selected. A normal oral dosage range is from about 300 mg. to about 3 g. per day in human patients calculated on the amount of piperidine. The definitive amount which is actually administered will be determined by the expertise of the extending clinician. He will be guided by the skills of his art in prescribing an amount sufiicient to attain normalization of the subject. These amounts are very low in view of the extremely low toxicity of the piperidine salts. The low toxicity is well known from the art and is further demonstrated by the observation that at doses of 1-3 g. of the hydrochloride daily to human patients no change in blood or liver can be observed nor are there any major side-effects. In contrast to treatments involving many other chemicals for treatments of mental disturbances, no depressions are caused by the new treatment, nor do the piperidine salts cause any lethargy, drowsiness, or impairment of motor function and coordination.

The eifects of the new treatment of mentally disturbed subjects with non-toxic, dissociable piperidine acid addition salts are those of calming and relief from hallucinations. Surprising results are observed with these chemopsychotherapeutic agents in neuropsychiatric patients. The new drugs normalize severely disturbed patients such as those in mental institutions for the criminally insane:

' the restlessness and hyperactivity of the patients are relieved, permitting an improvement in appetite and sleeping habits. The use of non-toxic piperidine salts in physiological dosage form not only produce general normalizing effects in the hyperactive patients, but also relieve anxiety and excessive mental tensions which may arise from a wide variety of sources such as gynecologic disorders, dermatological conditions, etc. The normalizing properties are those that refer to the pharmacodynamic property which, in animals, is exemplified by a decrease of aggressiveness and viciousness.

In the above discussion, the term normalize has been used. This term is meant to express the eifect of the drug as one which produces a more nearly normal behavior pattern in a mentally disturbed living subject. The term normalize is to be understood as a calming effect with relief from anxieties and hallucinations, without causing sedation, depression, or hypnosis. The term does not necessarily imply that a completely normal behavior can be created in a severely disturbed mental patient such as a schizophrenic, but that such mental disturbances are relieved to a high degree. freedom from confusion, calmness of mind, elimination of anxiety stages and hallucinations, or, in more severely disturbed subjects, reduced confusion, reduced passion, and reduced disturbances of mind without depression of mental faculties or clouding consciousness. The new drugs are also effective in the relief of just temporary depressionsand anxiety stages in otherwise normal subjects. Such effects are sometimes also referred to as those of tranquilization. Furthermore, these piperidine salts have been found to be effective muscle relaxants. The term muscle relaxant particularly refers to that property producing a pharmacological effect on the central nervous system which relieves skeletal muscle tension without affecting alertness. The compounds reduce muscle tone and counteract hallucinogenic agents and the behavioral changes produced by such agents.

Since the toxicity of the salts to which the present invention refers is extremely low, these salts may be administered orally to humans in relatively large doses, e.g., up to 3 g. per day in an adult human. All these amounts are based on free piperidine. The oral route of administration in animals shows that, where the stomach of the animal species is receptive, very high doses may be given. Mice and rats show no adverse results with 1000 mg./k-g. whereas dogs show emesis but no The new drug thus produces,

other eifects with 175" mg./kg. However, dogs given 17 and 35 mg./kg., respectively, per day over a period of several months show no undesirable elfects. Monkeys given 100. rag/kg. of drug show no effect but respond at a dose of 200 mg./kg. 'Ihe piperidine salts used in the method of the present invention are much more active when used in animals administered intraperitoneally. The effective dose in mice and rats is 35 m-g./ kg. while LD is about 180' rug/kg. In dogs, the efiective intraperitoneal dose is 100 rug/kg; in cats this dosage is about 75 mg/kg. and in double nephrectomized monkeys it is about 70 mg./kg. The LD in a double nephrectomized monkey is above 150' mg./kg.

To better illustrate the foregoing disclosure, reference is made to the following examples which are not to be considered the only applications of the new method.

EXAMPLE 1 which, due to the exothermicity of the reaction, started to reflux gently. The gas stream was continued until fuming ceased.' The mixture was then cooled to room temperature and the alcohol-insoluble piperidine-hydrochloride was isolated by filtration. The precipitate was Washed with isopropanol and dried at 50 C. in a vacuum oven. The pure salt, melting at 245-6 C., was obtained in a yield of 80-90% of theory.

A group of 11 patients in the ward of a mental institution was treated with the above piperidine hydrochloride. Each patient obtained 3 tablets per day with meals, the tablets being administered in form of gelatine capsules containing 500 mg. each of the above salt. Each patient showed reduced nervousness, better sleeping habits and improved appetite. In addition, the patients were better adjusted to the ward and more active. Although such patients usually complain about the side elfects of tranquilizing drugs, particularly new ones, these subjects stated that they would'like to continue this medication. Only a few patients reported very minor side effects such as mild emesis. The formerly hostile members of this group of patients became much less hostile, the others appeared more in contact with reality and more willing and able to enter into the total therapeutic program of the hospital.

' One of these patients who was extremely unmanageable and unwilling to take the tablets prescn'bed received 500 mg. of piperidine hydrochloride intramuscularly and showed signs of improvement 2. hours later. He became manageable so that the treatment could thereafter be continued with oral administration.

' EXAMPLE 2 j A group of rats was given 100 mtg/kg. of piperidine hydrochloride. intraperitoneally daily for 87 days. The weight curves of the rats were essentially the same as the weight curve of control rats throughout the test period.

After sacrificing the animals, lung, heart, aorta, spleen, liver, duodenum, gastrointestinal. tract, kidneys, and testes were histologically studied, but no significant findings were. observed,

EXAMPLE 3 A group of 50 chronically ill schizophrenics unable to verbalize well were treated by the dosage schedule given to the patients in Example 1. Some of these patients had a schizophrenic history extending'over a period of more than ten years.

The treatment reduced'and minimized outward expressions of hostility and aggressiveness; also, hallucinations were eliminated. The desirable effects were attained without any apparent signs of sedation or hypnosis. It was' with reality. More than half the patients so treated showed definite improvement.

EXAMPLE 4 A sterile solution containing 100 mg./cc. of piperidine hydrochloride was made up. The solution contained 70 mg./cc. of the free base. This solution was injected intr-aperitoneally at .a dose of 100 mg/kg. into rats which were made tense and vicious by keeping them in isolation and frequently depriving them of food and/ or Water. Within 15 minutes after the injection, the rats became relaxed, calm and easily manageable. They could be touched and handled easily by the animal keeper and exhibited marked muscle relaxation without a loss of muscle tone or impairment of reflexes. They also showed signs of ptosis which, however, was not caused by sleepiness since the animals so treated remained alert and active. Their tails became almost flaccid and the animals jumped much less when pain was induced such as by pinching their tails. No adverse effects were'observed.

The control rats were very tense, tried to bite the fingers of the animal keeper when he tried to touch them and even attacked a stick inserted into the cage. The control rats would kill other animals if brought into contact with them, whereas the rats after the treatment tolerated other animals in the cage in the usual manner. Both the test and control rats were healthy animals, 4 to 5 months of age. The tranquilizing eifect lasted about 90-120 minutes.

. The above experiment was repeated with piperidine phosphate, monopiperidine sulfate, dipiperdine sulfate, piperidine phthalate, piperidine tartrate, piperidine citrate, monopiperidine phosphate, dipipen'dine succinate, monopiperidine succinate, monopiperidine tartrate, dipiperidine tartrate, and piperidine maleate at the same piperidine concentration of 70 mg./kg. The effects observed with these salts were analogous to the effects described above.

EXAMPLE 5 A group of rats was conditioned to an electroshock box. In such a box, the animal gets an electric shock at 10 second intervals, but trained animals avoid the shock by jumping to a ledge. These animals were treated with the hallucinogen N-methyl-3-piperidyldiphenylglycolate which confused them to such a degree that they no longer were able to avoid the shocks. The effect of the hallucinogen was compensated by intraperitoneal injection of 5 0 mg./kg. of piperidine hydrochloride in aqueous solution 5 minutes prior to the administration'of the hallucinogen: the animals again jumped to the safe ledge before the electroshock.

This experimentshows the antagonistic effect of the piperidine salt to induced hyperactivity and confusion of mind caused by a hallucinogen.

EXAMPLE 6 A group of rats was kept individually in activity measurement cages. These cages are constructed in such a manner that the animals movements produce oscillations which are registered on a counter. The normal count of a healthy control rat averages about in a 5 minute period; After treating the rats with 5 mg./kg. of N- 5 EXAMPLE 7 A manic patient with the typical symptoms of destructiveness, who was incapable of maintaining any job and who was hypersexual, hyperirritable, aggressive, combative, destructive and had the other usual typical manic symptoms for one year in spite of treatments with known chemical tranquilizers, was given 4 daily doses of piperidine hydrochloride tablets, each tablet containing 500 mg. Within one week, the above mentioned typical symptoms disappeared and the patient became calm, rational, and almost completely integrated into normal life. The patient continues to do well on the medication 3 months later and is being considered for discharge from the mental institution.

EXAMPLE 8 Piperidine Hydrochloride Tablets Due to the hygroscopicity of piperidine hydrochloride, it was necessary to build some protection from moisture vapor into the formulation. For tablets containing 500 mg. of piperidine hydrochloride the following materials were used for subcoating:

Concentration per Ingredient For 1,000 Tablet Tablets, g.

Piperidine Hydrochloride 500.0

Corn Starch Powder 27. 5

Distilled Water to make Starch 65.

Paste. Oab-O-Sil, M- (a Silicate marketed by Cabot Inc). Magnesium Stearate 5. 5

Total dry weight The piperidine hydrochloride was ground to 30 mesh size and mixed with hot starch paste. The mixture was granulated through a 6 mesh screen and dried for 36 hours at 50 C. After drying, the mass was ground to 16 mesh size and charged into a blender where it was mixed with Cab-O-Sil and the magnesium stearate for 30 minutes. The mixture was then compressed into /2 inch convex bisected tablets which were charged into a coating pan. They were coated with 20% w/v. solution of polyvinylpyrrolidone in alcohol. During the coating process, the tablets were dusted with talcum powder to prevent stickiness and the tablets were subsequently dried for 24 hours at 25 C.

After this subcoating, the tablets were film-coated with the following solution.

Acetone, suflicient to make 1000.0 cc.

The tablets were placed in a coating pan and coated in the usual manner with 120 cc. of the above solution per pound of tablets. The tablets were subsequently dried in air at 25 C. for 16 hours and finally at 50 for 24 hours.

EXAMPLE 9 To a 250 cc. flask equipped with a condenser, an additional funnel, and a mechanical stirrer and containing 50 cc. of acetone, 8.5 g. phosphoric acid, and 1.5 g. of water was dropwise added 7.4 g. piperidine through the addition funnel at a rate producing gentle reflux. After completion of the addition, the mixture was cooled, filtered, and the precipitate washed with 20 cc. of acetone. The white crystals obtained were dried and represented 14.1 g. (88% of theory) of piperidine phosphate in form of white crystals melting at 2035-2050. After recrystallization from methanol/isopropanol, the same melting point was found. The calculated analytical values for piperidine dihydrogen phosphate are 32.79% C., 7.71% H., and 7.65% N. The analytical values of the piperidine phosphate made in the above manner was 33.00% C., 7.76% H., and 7.65% N.

EXAMPLE 10 Piperia'ine Phosphate Tablets In a 115 liter glass-lined still, 83.27 liters of acetone and 17.78 kg. of phosphoric acid water) were mixed by an agitator. To this mixture was added 13.15 kg. of piperidine over a period of about 2 hours allowing the reaction mixture to come to a gentle reflux. After completion of the addition, the mixture was stirred for another hour, cooled, and centrifuged. 'The solid material obtained in this manner was resl-urried in 35 liters of acetone and 'again centrifuged. The White crystals obtained were dried in an air dryer at 80-90 C., producing a yield of 26.3 kg. (93.5% of theory) of piperidine phosphate with a melting point of 204.0-205.8 C.

To make Scale/Tablet Ingredient tablets, g.

537.7 mg. Piperidine Phosphate (464.94 537. 7

mg. Piperidine per gram).

4 Sodium carb0xymethylcellulose 25.9 Distilled Water 90. 0 Talcum Powder 13.0 Magnesium Stearate 6. 6 Corn Starch Powder 64. 8

Total Dry Weight. 647. 9

The piperidine phosphate was ground to 30 mesh size and blended for 20 minutes with the sodium carboxymethylcellulose which was previously ground to 40 mesh size. The mixture was massed with water, granulated through a 6 mesh screen and dried 24 hours at 50 C. The dried mixture was granulated to 16 mesh, charged into a blender and blended 30 minutes with the mixture of talcum powder, magnesium stearate, and corn starch previously ground through a 40 mesh screen. After thorough blending, the powder was compressed into /2 inch convex tablets and these tablets were coated with the coating solution of Example 7 but without previous subcoating. Each tablet contained 250 mg. of the piperidine base or 537.7 mg. of piperidine phosphate.

From the above, it will be seen that the new method of treating mental tensions and anxieties shows surprising results. These results are particularly striking in view of the simplicity of the treatment, the ease of its administration, and the economics of the compounds involved. These compounds, as outlined above, are acid addition salts of piperidine with easily dissociable, non-toxic acids such as hydrochloric, surfuric, phosphoric, succinic, tartaric, citric, phthalic, maleic, ascorbic, furnaric, and acetic acid as well as similar acids which fit the above defining limitation.

In the above discussion, all amounts have been based on the amount of free piperidine, the actual effective portion of the salts, unless it was specifically pointed out that the weight of the salt was cited. The preferred oral human dose, for example, is 1-3 g. per day of piperidine hydrochloride which amounts to 0.7-2.1 g. per day of the free base or to 1.5-4.5 g. per day of monopiperidine phosphate. The upper limits may safely be raised by about 50 60% without producing any serious side eifects, and the lower limits may be reduced to about half the amounts stated above for the treatment of only mild stages of anxiety and/0r tension. Thus, the total effective oral daily dose for humans ranges from about 0.3 g. to about 3.0 g. of free piperidine which, in the form of the hydrochloride would be from about 0.43 g. to about 4.3 g. and in the form of the dihydrogen phosphate salt from about 0.65 g. to about 6.5 g.

- Although all'the above and similar addition saltsare equally useful for the treatment of mental disorders and psychic disturbances, those in which the acid is'imonobasic and! or has a low moleculariweight are preferred."

phoric acid addition salt is inthis preferred group, in spite of its relatively large molecule because it not only does not introduce a foreign acid into the body fluids, but it is exceptional in its inherent property of not being hygroscopic. The monopiperidine phosphate is thus preferred.

since it can be tableted much easier without requiring any protective coating. The pressed monopiperidine phosphate makes a coherent, nonhygroscopic, form-stable tablet that may easily be coated if desired.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

' I claim:

' 1. A method of reducing and in some cases eliminating the outward signs of hostility and paranoid tendencies evidenced by aggression, combativeness and belligerency and certain types of Withdrawal and detachment engendered by hostility, without causing central nervous system depression or sedation, in mentally ill human subjects in whom the aforementioned signs are evidenced, comprising orally'administering to said patient about 0.3 g. to about 3.0 g. of piperidine per day in the form of a non-toxic, dissociable acid addition salt thereof.

2. The method of claim 1 wherein said salt of piperi- 3. The method of claim 1 wherein said salt of piperidine is monopiperidine hydrochloride.

4. A method of reducing and in some cases eliminat v ing the outward signs of hostility and paranoid tendencies V evidenced by aggression, combativene'ss and belligerency and certain types of Withdrawal and detachment engendered by hostility, without causing central nervoussystern depression'or sedation, in mentally. ill human subjects in whom the aforementioned signs are evidenced, comprising orally administering to said patient a composition containing from about 0.7 to about 2.1 got a non-toxic, dissociable, acid addition salt of piperidine and a pharmaceutical carrier.

5. The method of claim 4 wherein said pharmaceutical carrier is a solid.

6. The method of claim 5 wherein said salt of pipcridine and said solid pharmaceutical carrier are placed together in tablet form.

References Cited in the file of this patent UNITED STATES PATENTS 2,490,098 Simons Dec. 6, 1949 2,590,126

2,872,374 Beiler Feb. 3, 1959 OTHER REFERENCES Chem. Abst. Decennial Index (1937-1946), pp. 8087- 8088.

Sollmann: A Manual of Pharmacology, 8th ed., 1957, pp. 458, 467. e

Macht: ChemQAbs. 15, 397(1), 1921. Novello: Chem. Abs. 20, 3030(5), 1926. Houssay: Chem. Abs. 20, 1862(4), 1926. Ellis i Science, 114, 325-6, 1951.

Robinson Mar. 25, 1952 

1. A METHOD OF REDUCING AND IN SOME CASEE ELIMINATING THE OUTWARD SIGNS OF HOSTILITY AND PARANOID TENDENCIES EVIDENCED BY AGGRESSION, COMBATIVENESS AND BELLIGERENCY AND CERTAIN TYPES OF WITHDRAWAL AND DETACHMENT ENGENDERED BY HOSTILITY, WITHOUT CAUSING CENTRAL NERVOUS SYSTM DEPRESSION OR SEDATION, IN MENTALLY ILL HUMAN SUBJECTS IN WHOM THE AFOREMENTIONED SIGNS ARE EVIDENCE COMPRISING ORALLY ADMINISTERING TO SAID PATIENT ABOUT 0.3 G TO ABOUT 3.0 G OF PIPERIDINE PER DAY IN THE FORM OF A NON-TOXIC, DISSOCIABLE ACID ADDITION SALT THEREOF. 